UC San Diego

Nature is the source of an incredible diversity of complex chemistry. The wide variety of chemical scaffolds produced as secondary metabolites have been the source of many useful medicinal therapies for the treatment of human disease, in addition to providing useful tools for probing biology. The biosynthetic machinery that produces these molecules is encoded in the genomes of organisms, and recent technological advancements in bioinformatics, DNA sequencing, and gene cloning and capture techniques offer researchers new opportunities for natural products discovery. When combined with modern analytical chemistry techniques, these methods are a powerful engine for compound discovery. The marine environment represents a unique well of biodiversity to investigate with this new methodology, with a unique evolutionary history ancient than terrestrial habitats. Chapter 2 of this dissertation describes the in-depth analysis of a collection of 146 marine actinomycetes by mass spectrometry and molecular networking to investigate their biosynthetic capacity. These bacteria were cultured in a variety of media, and their extracts were used to generate approximately 1.8 million mass spectra. Analysis of this large data set was accomplished by the Global Natural Product Social Molecular Networking platform, which allowed for the identification of known metabolites and revealed information about the production of novel metabolites. Chapter 3 of this dissertation presents a more focused study on a single biosynthetic gene cluster from an ocean streptomycete, which produces a suite of glycosylated anthracyclines. In addition to revealing the biosynthetic source of the cosmomycins and describing novel analogs of these compounds, this study describes a novel PCR-independent gene capture method utilizing the recent advances in gene synthesis technology. In Chapter 4 of this dissertation, a phosphonate biosynthetic gene cluster from another marine actinomycete, Salinispora pacifica, was investigated for small molecule production. Analysis of this gene cluster revealed the production of glyphosate degradation products, previously assumed to be anthropogenic pollutants. Bacterial production of these molecules has important implications for environmental study and monitoring of phosphonate pollutants.